Traumatic brain injury (TBI) curtails quality of life by compromising cognitive function. We hypothesize that reduced cognitive capacity following TBI is the result of dysfunction in the molecular mechanisms that support synaptic plasticity. This compromises the capacity of cells to process, transmit, and store information, thereby ultimately affecting higher order functions such as learning and memory. Brain-derived neurotrophic factor (BDNF) has a critical action in all of these events - thus, we propose a physiological means to modulate the capacity of the brain to compensate for secondary insults, by using BDNF as a central mechanism. Encouraged by our original findings that physical activity induces BDNF in the intact brain, we propose that exercise can be employed to improve functional recovery after TBI. It is, therefore, a central goal of this proposal to link exercise with neurotrophins and optimize the exercise-induced expression of endogenous BDNF that can boost functional recovery following brain trauma. Emerging evidence suggests that trophic interactions driven by neural activity mediate diverse processes, such as neuronal resilience and synaptic function, that may underlie CNS healing and learning/memory. An important and novel aspect of our paradigm incorporates the finding that, in addition to helping neuronal survival, BDNF plays a significant role in synaptic plasticity. Given that our main objective is to apply exercise to benefit the TBI condition, the design of our studies takes into consideration how the period of energy crisis, characterizing the acute phase of the traumatically injured brain, may interfere with exercise. A positive outcome of these studies would open a new line of therapeutic treatments for TBI patients that upregulates endogenous neurotrophins. Most intervention procedures for TBI have focused on adding exogenous substances into the brain, thereby ignoring the intrinsic capacity of the brain for plasticity. Given that the majority of clinical trials have not resulted in a positive effect on outcome, we feel it is time to re-think the concept of inducing recovery of function. Therefore, the unique aspect of our proposal is to evaluate experience as a modulator of neuronal plasticity that can be used to enhance functional recovery following TBI.